Abstract
ABSTRACTMicroglial activation occurs in divergent neuropathological conditions. Such microglial event has the key involvement in the progression of CNS diseases. However, the transcriptional mechanism governing microglial activation remains poorly understood. Here, we investigate the microglial response to traumatic injury-induced neurodegeneration by the 3D fluorescence imaging technique. We show that transcription factors IRF8 and PU.1 are both indispensible for microglial activation, as their specific post-developmental deletion in microglia abolishes the process. Mechanistically, we reveal that IRF8 and PU.1 directly target the gene transcription of each other in a positive feedback to sustain their highly enhanced expression during microglial activation. Moreover, IRF8 and PU.1 dictate the microglial response by cooperatively acting through the composite IRF-ETS motifs that are specifically enriched on microglial activation-related genes. This action of cooperative transcription can be further verified biochemically by the synergetic binding of IRF8 and PU.1 proteins to the composite-motif DNA. Our study has therefore elucidated the central transcriptional mechanism of microglial activation in response to neurodegenerative condition.
Highlights
As the specialized immune cells of the central nervous system (CNS), microglia participate in diverse physiological and disease processes
We have exploited the 3D fluorescence imaging to investigate the microglial response to neurodegeneration
The 3D fluorescence imaging could be readily extended to examine a variety of glial events in neural tissues beyond the optic nerves, e.g., brain and spinal cord, which would certainly assist in the comprehensive characterization of different CNS diseases
Summary
As the specialized immune cells of the central nervous system (CNS), microglia participate in diverse physiological and disease processes. Microglia exert essential functions in brain development, e.g., in the precise establishment of neural connections (Stephan et al, 2012; Aguzzi et al, 2013; Kettenmann et al, 2013; Schafer and Stevens, 2015; Hong et al, 2016). This glial population is indispensible for maintenance of the neural homeostasis throughout adulthood (Prinz and Priller, 2014; MichellRobinson et al, 2015; Prinz et al, 2017; Tay et al, 2017). Our in-depth knowledge of the microglial activation would help reveal therapeutic targets for treatment of the debilitating CNS diseases (Biber et al, 2016; Colonna and Butovsky, 2017; Herz et al, 2017)
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